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Background and Hypothesis Hallucinations may be driven by an excessive influence of prior expectations on current experience. Initial work has supported that contention and implicated the anterior insula in the weighting of prior beliefs. Study Design Here we induce hallucinated tones by associating tones with the presentation of a visual cue. We find that people with schizophrenia who hear voices are more prone to the effect and using computational modeling we show they overweight their prior beliefs. In the same participants, we also measured glutamate levels in anterior insula, anterior cingulate, dorsolateral prefrontal, and auditory cortices, using magnetic resonance spectroscopy. Study Results We found a negative relationship between prior-overweighting and glutamate levels in the insula that was not present for any of the other voxels or parameters. Conclusions Through computational psychiatry, we bridge a pathophysiological theory of psychosis (glutamate hypofunction) with a cognitive model of hallucinations (prior-overweighting) with implications for the development of new treatments for hallucinations. [ABSTRACT FROM AUTHOR]

Objectives Negative symptom studies frequently use single composite scores as indicators of symptom severity and as primary endpoints in clinical trials. Factor analytic and external validation studies do not support this practice but rather suggest a multidimensional construct. The current study used structural equation modeling (SEM) to compare competing dimensional models of negative symptoms to determine the number of latent dimensions that best capture variance in biological, psychological, and clinical variables known to have associations with negative symptoms. Methods Three independent studies (total n = 632) compared unidimensional, two-factor, five-factor, and hierarchical conceptualizations of negative symptoms in relation to cognition, psychopathology, and community functioning (Study 1); trait emotional experience and defeatist performance beliefs (Study 2); and glutamate and gamma-aminobutyric acid levels in the anterior cingulate cortex quantified using proton magnetic resonance spectroscopy (Study 3). Results SEM favored the five-factor and hierarchical models over the unidimensional and two-factor models regardless of the negative symptom measure or external validator. The five dimensions—anhedonia, asociality, avolition, blunted affect, and alogia—proved vital either as stand-alone domains or as first-order domains influenced by second-order dimensions—motivation and pleasure and emotional expression. The two broader dimensions sometimes masked important associations unique to the five narrower domains. Avolition, anhedonia, and blunted affect showed the most domain-specific associations with external variables across study samples. Conclusions Five domains and a hierarchical model reflect the optimal conceptualization of negative symptoms in relation to external variables. Clinical trials should consider using the two dimensions as primary endpoints and the five domains as secondary endpoints. [ABSTRACT FROM AUTHOR]

Proton magnetic resonance spectroscopy (MRS) studies in schizophrenia have shown altered GABAergic, glutamatergic, and bioenergetic pathways, but if these abnormalities are brain region or illness-stage specific is largely unknown. MRS at 7T MR enables reliable quantification of multiple metabolites, including GABA, glutamate (Glu) and glutamine (Gln), from multiple brain regions within the time constraints of a clinical examination. In this study, GABA, Glu, Gln, the ratio Gln/Glu, and lactate (Lac) were quantified using 7T MRS in five brain regions in adults with schizophrenia (N = 40), first-degree relatives (N = 11), and healthy controls (N = 38). Metabolites were analyzed for differences between groups, as well as between subjects with schizophrenia with either short (<5 years, N = 19 or long (>5 years, N = 21) illness duration. For analyses between the three groups, there were significant glutamatergic and GABAergic differences observed in the anterior cingulate, centrum semiovale, and dorsolateral prefrontal cortex. There were also significant relationships between anterior cingulate cortex, centrum semiovale, and dorsolateral prefrontal cortex and cognitive measures. There were also significant glutamatergic, GABAergic, and lactate differences between subjects with long and short illness duration in the anterior cingulate, centrum semiovale, dorsolateral prefrontal cortex, and hippocampus. Finally, negative symptom severity ratings were significantly correlated with both anterior cingulate and centrum semiovale metabolite levels. In summary, 7T MRS shows multi-region differences in GABAergic and glutamatergic metabolites between subjects with schizophrenia, first-degree relatives and healthy controls, suggesting relatively diffuse involvement that evolves with illness duration. Unmedicated first-degree relatives share some of the same metabolic characteristics as patients with a diagnosis of schizophrenia, suggesting that these differences may reflect a genetic vulnerability and are not solely due to the effects of antipsychotic interventions. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental illness with visual learning and memory deficits, and reduced long term potentiation (LTP) may underlie these impairments. Recent human fMRI and EEG studies have assessed visual plasticity that was induced with high frequency visual stimulation, which is thought to mimic an LTP-like phenomenon. This study investigated the differences in visual plasticity in participants with schizophrenia and healthy controls. An fMRI visual plasticity paradigm was implemented, and proton magnetic resonance spectroscopy data were acquired to determine whether baseline resting levels of glutamatergic and GABA metabolites were related to visual plasticity response. Adults with schizophrenia did not demonstrate visual plasticity after family-wise error correction; whereas, the healthy control group did. There was a significant regional difference in visual plasticity in the left visual cortical area V2 when assessing group differences, and baseline GABA levels were associated with this specific ROI in the SZ group only. Overall, this study suggests that visual plasticity is altered in schizophrenia and related to basal GABA levels. [ABSTRACT FROM AUTHOR]

Sleep dysfunction is prevalent among patients with schizophrenia. Although sex differences have been identified in schizophrenia, sex differences in sleep patterns among patients with schizophrenia are not established. Therefore, the current study examined sex differences in subjective sleep quality patterns in people with schizophrenia utilizing a standardized inventory. Study sample consisted of 75 patients with schizophrenia and 82 healthy controls (HC). Participants completed the Pittsburgh Sleep Quality Index (PSQI). Compared to HC, patients with schizophrenia were more likely to report being poor sleepers (PSQI global score > 5), longer sleep duration, more sleep disturbances, longer sleep onset latency, increased daytime dysfunction due to poor sleep, and more frequent use of sleep medications. Regarding sex differences, female patients were more likely to report being poor sleepers and endorsed more sleep disturbances than female HC, while male patients reported longer sleep duration, more daytime dysfunction, and poorer overall sleep quality relative to male HC. Additionally, higher level of sleep dysfunction was linked to higher symptom severity in male patients only. Patients with schizophrenia endorsed a range of sleep difficulties, and male and female patients with schizophrenia differ compared to their HC counterparts. Implications for treatment of sleep complaints among patients with schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

Although schizophrenia is a brain disorder, increasing evidence suggests that there may be body-wide involvement in this illness. However, direct evidence of brain structures involved in the presumed peripheral-central interaction in schizophrenia is still unclear. Seventy-nine previously treatment-naïve first-episode schizophrenia patients who were within 2-week antipsychotics initial stabilization, and 41 age- and sex-matched healthy controls were enrolled in the study. Group differences in subcortical brain regional structures measured by MRI and the subclinical cardiovascular, metabolic, immune, and neuroendocrine biomarkers as indexed by allostatic load, and their associations were explored. Compared with controls, patients with schizophrenia had significantly higher allostatic load (P =.001). Lateral ventricle (P <.001), choroid plexus (P <.001), and thalamus volumes (P <.001) were significantly larger, whereas amygdala volume (P =.001) was significantly smaller in patients. The choroid plexus alone was significantly correlated with higher allostatic load after age, sex, education level, and the total intracranial volume were taken into account (t = 3.60, P <.001). Allostatic load was also significantly correlated with PANSS positive (r = 0.28, P =.016) and negative (r = −0.31, P =.008) symptoms, but in opposite directions. The peripheral multisystemic and central nervous system abnormalities in schizophrenia may interact through the choroid plexus during the early stage of the illness. The choroid plexus might provide a sensitive structural biomarker to study the treatment and prevention of brain-periphery interaction abnormalities in schizophrenia. [ABSTRACT FROM AUTHOR]

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10−3), auditory network (d: 0.67 ± 0.26, p =.04) and default mode network (DMN, d: 0.63 ± 0.26, p =.05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p =.03). The effect sizes for ketamine for resting networks showed a positive correlation (r =.59, p =.07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = −.17, p =.65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r =.68, p =.03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug. [ABSTRACT FROM AUTHOR]

Cognitive deficits contribute to functional disability in patients with schizophrenia and may be related to altered functional networks that serve cognition. We evaluated the integrity of major functional networks and assessed their role in supporting two cognitive functions affected in schizophrenia: processing speed (PS) and working memory (WM). Resting‐state functional magnetic resonance imaging (rsfMRI) data, N = 261 patients and 327 controls, were aggregated from three independent cohorts and evaluated using Enhancing NeuroImaging Genetics through Meta Analysis rsfMRI analysis pipeline. Meta‐ and mega‐analyses were used to evaluate patient‐control differences in functional connectivity (FC) measures. Canonical correlation analysis was used to study the association between cognitive deficits and FC measures. Patients showed consistent patterns of cognitive and resting‐state FC (rsFC) deficits across three cohorts. Patient‐control differences in rsFC calculated using seed‐based and dual‐regression approaches were consistent (Cohen's d: 0.31 ± 0.09 and 0.29 ± 0.08, p < 10−4). RsFC measures explained 12–17% of the individual variations in PS and WM in the full sample and in patients and controls separately, with the strongest correlations found in salience, auditory, somatosensory, and default‐mode networks. The pattern of association between rsFC (within‐network) and PS (r =.45, p =.07) and WM (r =.36, p =.16), and rsFC (between‐network) and PS (r =.52, p = 8.4 × 10−3) and WM (r =.47, p =.02), derived from multiple networks was related to effect size of patient‐control differences in the functional networks. No association was detected between rsFC and current medication dose or psychosis ratings. Patients demonstrated significant reduction in several FC networks that may partially underlie some of the core neurocognitive deficits in schizophrenia. The strength of connectivity‐cognition relationships in different networks was strongly associated with network's vulnerability to schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Failure of antipsychotic medications to resolve symptoms in patients with schizophrenia creates a clinical challenge that is known as treatment resistance. The causes of treatment resistance are unknown, but it is associated with earlier age at onset and more severe cognitive deficits. The authors tested the hypothesis that white matter deficits that are involved in both neurodevelopment and severity of cognitive deficits in schizophrenia are associated with a higher risk of treatment resistance.Methods: The study sample (N=122; mean age, 38.2 years) included schizophrenia patients at treatment initiation (N=45), patients whose symptoms were treatment responsive (N=40), and patients whose symptoms were treatment resistant (N=37), as well as healthy control subjects (N=78; mean age, 39.2 years). White matter regional vulnerability index (RVI) was tested as a predictor of treatment resistance and cognitive deficits. Higher RVI is indicative of better agreement between diffusion tensor imaging fractional anisotropy across the brain in an individual and the pattern identified by the largest-to-date meta-analysis of white matter deficits in schizophrenia.Results: Patients with treatment-resistant symptoms showed the highest white matter RVI (mean=0.38 [SD=0.2]), which was significantly higher than the RVI among patients with treatment-responsive symptoms (mean=0.30 [SD=0.02]). At the onset of treatment, schizophrenia patients showed significantly higher RVI than healthy control subjects (mean=0.18 [SD=0.03] and mean=0.13 [SD=0.02], respectively). RVIs were significantly correlated with performance on processing speed and negative symptoms.Conclusions: Schizophrenia affects white matter microstructure in specific regional patterns. Susceptibility to white matter regional deficits is associated with an increased likelihood of treatment resistance. Developments to overcome schizophrenia treatment resistance should consider white matter as an important target. [ABSTRACT FROM AUTHOR]

Negative symptoms represent a distinct component of psychopathology in schizophrenia (SCZ) and are a stable construct over time. Although impaired frontostriatal connectivity has been frequently described in SCZ, its link with negative symptoms has not been carefully studied. We tested the hypothesis that frontostriatal connectivity at rest may be associated with the severity of negative symptoms in SCZ. Resting state functional connectivity (rsFC) data from 95 mostly medicated patients with SCZ and 139 healthy controls (HCs) were acquired. Negative symptoms were assessed using the Brief Negative Symptom Scale. The study analyzed voxel-wise rsFC between 9 frontal "seed regions" and the entire striatum, with the intention to reduce potential biases introduced by predefining any single frontal or striatal region. SCZ showed significantly reduced rsFC between the striatum and the right medial and lateral orbitofrontal cortex (OFC), lateral prefrontal cortex, and rostral anterior cingulate cortex compared with HCs. Further, rsFC between the striatum and the right medial OFC was significantly associated with negative symptom severity. The involved striatal regions were primarily at the ventral putamen. Our results support reduced frontostriatal functional connectivity in SCZ and implicate striatal connectivity with the right medial OFC in negative symptoms. This task-independent resting functional magnetic resonance imaging study showed that medial OFC–striatum functional connectivity is reduced in SCZ and associated with severity of negative symptoms. This finding supports a significant association between frontostriatal connectivity and negative symptoms and thus may provide a potential circuitry-level biomarker to study the neurobiological mechanisms of negative symptoms. [ABSTRACT FROM AUTHOR]

Background The underlying neurobiological mechanism for abnormal functional connectivity in schizophrenia (SCZ) remains unknown. This project investigated whether glutamate and GABA, 2 metabolites that contribute to excitatory and inhibitory functions, may influence functional connectivity in SCZ. Methods Resting-state functional magnetic resonance imaging and proton magnetic resonance spectroscopy were acquired from 58 SCZ patients and 61 healthy controls (HC). Seed-based connectivity maps were extracted between the anterior cingulate cortex (ACC) spectroscopic voxel and all other brain voxels. Magnetic resonance spectroscopy (MRS) spectra were processed to quantify glutamate and GABA levels. Regression analysis was performed to describe relationships between functional connectivity and glutamate and GABA levels. Results Reduced ACC functional connectivity in SCZ was found in regions associated with several neural networks including the default mode network (DMN) compared to HC. In the HC, positive correlations were found between glutamate and both ACC—right inferior frontal gyrus functional connectivity and ACC—bilateral superior temporal gyrus functional connectivity. A negative correlation between GABA and ACC—left posterior cingulate functional connectivity was also observed in HC. These same relationships were not statistically significant in SCZ. Conclusions The present investigation is one of the first studies to examine links between functional connectivity and glutamate and GABA levels in SCZ. Results indicate that glutamate and GABA play an important role in the functional connectivity modulation in the healthy brain. The absence of glutamate and GABA correlations in areas where SCZ showed significantly reduced functional connectivity may suggest that this chemical-functional relationship is disrupted in SCZ. [ABSTRACT FROM AUTHOR]

Regulation of stress response involves top-down mechanisms of the frontal-limbic glutamatergic system. As schizophrenia is associated with glutamatergic abnormalities, we hypothesized that schizophrenia patients may have abnormal glutamatergic reactivity within the dorsal anterior cingulate cortex (dACC), a key region involved in perception of and reaction to stress. To test this, we developed a somatic stress paradigm involving pseudorandom application of safe but painfully hot stimuli to the forearm of participants while they were undergoing serial proton magnetic resonance spectroscopy to measure changes in glutamate and glutamine levels in the dACC. This paradigm was tested in a sample of 21 healthy controls and 23 patients with schizophrenia. Across groups, glutamate levels significantly decreased following exposure to thermal pain, while ratio of glutamine to glutamate significantly increased. However, schizophrenia patients exhibited an initial increase in glutamate levels during challenge that was significantly different from controls, after controlling for heat pain tolerance. Furthermore, in patients, the acute glutamate response was positively correlated with childhood trauma (r = .41, P = .050) and inversely correlated with working memory (r = -.49, P = .023). These results provide preliminary evidence for abnormal glutamatergic response to stress in schizophrenia patients, which may point toward novel approaches to understanding how stress contributes to the illness. [ABSTRACT FROM AUTHOR]

Background: Delta band (1-4 Hz) neuronal responses support the precision and stability of auditory processing, and a deficit in delta band synchrony may be relevant to auditory domain symptoms in schizophrenia patients. Methods: Delta band synchronization elicited by a 2.5 Hz auditory steady state response (ASSR) paradigm, along with those from theta (5 Hz), alpha (10 Hz), beta (20 Hz), gamma (40 Hz), and high gamma (80 Hz) frequency ASSR, were compared in 128 patients with schizophrenia, 108 healthy controls, and 55 first-degree relatives (FDR) of patients. Results: Delta band synchronization was significantly impaired in patients compared with controls (F = 18.3, P < .001). There was a significant 2.5 Hz by 40 Hz ASSR interaction (P = .023), arising from a greater reduction of 2.5 Hz ASSR than of 40 Hz ASSR, in patients compared with controls. Greater deficit in delta ASSR was associated with auditory perceptual abnormality (P = .007) and reduced verbal working memory (P < .001). Gamma frequency ASSR impairment was also significant but more modest (F = 8.7, P = .004), and this deficit was also present in FDR (P = .022). Conclusions: The ability to sustain delta band oscillation entrainment in the auditory pathway is significantly reduced in schizophrenia patients and appears to be clinically relevant. [ABSTRACT FROM AUTHOR]

Patients with schizophrenia are often plagued by sleep disturbances that can exacerbate the illness, including potentiating psychosis and cognitive impairments. Cognitive dysfunction is a core feature of schizophrenia with learning and memory being particularly impaired. Sleep disruptions often accompanying the illness and may be key mechanism that contribute to these core dysfunctions. In this special translational neuroscience feature, we highlight the role of sleep in mediating cognitive function, with a special focus on learning and memory. By defining dysfunctional sleep architecture and rhythms in schizophrenia, we focus on the disarray of mechanisms critical to learning and memory and postulate an association between sleep disturbances and cognitive impairments in the disorder. Lastly, we review preclinical models of schizophrenia and highlight exciting translational research that may lead to new therapeutic approaches to alleviating sleep disturbances and effectively improving cognitive function in schizophrenia. [ABSTRACT FROM AUTHOR]

Importance: Efforts to remediate the multiple cognitive function impairments in schizophrenia should consider white matter as one of the underlying neural mechanisms.Objective: To determine whether altered structural brain connectivity is responsible for 2 of the core cognitive deficits in schizophrenia- reduced information processing speed and impaired working memory.Design, Setting, and Participants: This cross-sectional study design took place in outpatient clinics from August 1, 2004, to August 31, 2015. Participants included 166 patients with schizophrenia and 213 healthy control individuals. These participants were from 3 independent cohorts, each of which had its own healthy control group. No participant had current or past neurological conditions or major medical conditions. Patients were diagnosed with either schizophrenia or schizoaffective disorder as defined by the DSM-IV. Controls had no Axis I psychiatric disorder.Main Outcomes and Measures: Mediation analyses and structural equation modeling were used to analyze the associations among processing speed, working memory, and white matter microstructures. Whole-brain and regional diffusion tensor imaging fractional anisotropy were used to measure white matter microstructures.Results: Of the study participants, the 166 patients with schizophrenia had a mean (SD) age of 38.2 (13.3) years and the 213 healthy controls had a mean (SD) age of 39.2 (14.0) years. There were significantly more male patients than controls in each of the 3 cohorts (117 [70%] vs 91 [43%]), but there were no significant differences in sex composition among the 3 cohorts. Patients had significantly reduced processing speed (Cohen d = 1.24; P = 6.91 × 10-30) and working memory deficits (Cohen d = 0.83; P = 1.10 × 10-14) as well as a significant whole-brain fractional anisotropy deficit (Cohen d = 0.63; P = 2.20 × 10-9). In schizophrenia, working memory deficit was mostly accounted for by processing speed deficit, but this deficit remained when accounting for working memory (Cohen d = 0.89; P = 2.21 × 10-17). Mediation analyses showed a significant association pathway from fractional anisotropy to processing speed to working memory (P = 5.01 × 10-7). The strength of this brain-to-cognition pathway in different white matter tracts was strongly associated with the severity of schizophrenia-associated fractional anisotropy deficits in the corresponding white matter tracts as determined by a meta-analysis (r = 0.85-0.94; all P < .001). The same pattern was observed in patients and controls either jointly or independently.Conclusions and Relevance: Study findings suggest that (1) processing speed contributes to the association between white matter microstructure and working memory in schizophrenia and (2) white matter impairment in schizophrenia is regional tract-specific, particularly in tracts normally supporting processing speed performance. [ABSTRACT FROM AUTHOR]

Inflammation may play a role in schizophrenia; however, subgroups with immune regulation dysfunction may serve as distinct illness phenotypes with potential different treatment and prevention strategies. Emerging data show that about 30% of people with schizophrenia have elevated antigliadin antibodies of the IgG type, representing a possible subgroup of schizophrenia patients with immune involvement. Also, recent data have shown a high correlation of IgG-mediated antibodies between the periphery and cerebral spinal fluid in schizophrenia but not healthy controls, particularly AGA IgG suggesting that these antibodies may be crossing the blood–brain barrier with resulting neuroinflammation. Proton magnetic resonance spectroscopy (MRS) is a non-invasive technique that allows the quantification of certain neurochemicals in vivo that may proxy inflammation in the brain such as myoinositol and choline-containing compounds (glycerophosphorylcholine and phosphorylcholine). The objective of this exploratory study was to examine the relationship between serum AGA IgG levels and MRS neurochemical levels. We hypothesized that higher AGA IgG levels would be associated with higher levels of myoinositol and choline-containing compounds (glycerophosphorylcholine plus phosphorylcholine; GPC + PC) in the anterior cingulate cortex. Thirty-three participants with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder had blood drawn and underwent neuroimaging using MRS within 9 months. We found that 10/33 (30%) had positive AGA IgG (≥20 U) similar to previous findings. While there were no significant differences in myoinositol and GPC + PC levels between patients with and without AGA IgG positivity, there were significant relationships between both myoinositol (r = 0.475, p = 0.007) and GPC + PC (r = 0.36, p = 0.045) with AGA IgG levels. This study shows a possible connection of AGA IgG antibodies to putative brain inflammation as measured by MRS in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Childhood abuse has been implicated as an environmental factor that increases the risk for developing schizophrenia. A recent large population-based case-control study found that abuse may be a risk factor for schizophrenia in women, but not men. Given the sex differences in onset and clinical course of schizophrenia, we hypothesized that childhood abuse may cause phenotypic differences in the disorder between men and women. Methods: We examined the prevalence of childhood physical abuse in a cohort of men and women with schizophrenia and schizoaffective disorder. Specifically, we examined differences in positive, negative, cognitive and depressive symptoms in men and women who reported a history of childhood physical abuse. We recruited 100 subjects for a single visit and assessed a history of childhood physical abuse using the childhood trauma questionnaire (CTQ) and clinical symptoms and cognition using the brief psychiatric rating scale (BPRS), the calgary depression scale (CDS) and the repeatable battery of the assessment of neuropsychological status (RBANS) for cognition. Results: Ninety-two subjects completed the full CTQ with abuse classified as definitely present, definitely absent or borderline. Twelve subjects who reported borderline abuse scores were excluded. Of the 80 subjects whose data was analyzed, 10 of 24 (41.6%) women and 11 of 56 (19.6%) men reported a history of childhood physical abuse (² = 4.21, df = 1, p = 0.04). Women who reported such trauma had significantly more psychotic (sex by abuse interaction; F = 4.03, df = 1.76, p = 0.048) and depressive (F = 4.23, df = 1.76, p = 0.04) symptoms compared to women who did not have a trauma history and men, regardless of trauma history. There were no differences in negative or cognitive symptoms. Conclusions: Women with schizophrenia and schizoaffective disorder may represent a distinct phenotype or subgroup with distinct etiologies and may require different, individually tailored treatments. [ABSTRACT FROM AUTHOR]

Importance: Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge.Objective: To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia.Design, Setting, and Participants: Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015.Main Outcomes and Measures: Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance.Results: The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia.Conclusions and Relevance: The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia. [ABSTRACT FROM AUTHOR]

Purpose To determine the reproducibility and reliability of glutamine (Gln), measured with a very short echo time phase rotation stimulated echo acquisition mode (VTE-PR STEAM) sequence at 3T, in subjects with schizophrenia. Methods Seven subjects with schizophrenia were scanned twice with VTE-PR STEAM in a Siemens 3T TIM Trio scanner with a 32-channel head coil. Spectroscopic data were collected from two voxels in gray matter, one in the dorsal anterior cingulate and the other in the medial occipital cortex. Reproducibility was assessed using coefficients of variation (CVs) and reliability with standard error of measurement and intraclass correlations (ICCs). Phantoms containing increasing concentrations of Gln in a physiologic solution of other neurometabolites with overlapping resonances were scanned to assess the validity of spectral Gln measurement. Results Very good reliability and reproducibility for Gln in both regions of interest were supported by CVs of ≤10.0% and ICCs of ≥0.6, respectively. Phantom studies documented a robust correspondence between known Gln concentrations and VTE-PR STEAM measurements of this metabolite (R2 = 0.988). Conclusion The VTE-PR STEAM approach at 3T permits the longitudinal assessment of Gln and other 1H MR spectroscopy neurometabolites in a clinically plausible setting. Magn Reson Med 75:498-502, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Depression is highly prevalent in patients with schizophrenia and is associated with significant clinical consequences, but there is no known biomarker for depression in schizophrenia. One of the putative neurochemical biomarkers for depression in major depressive disorder (MDD) is reduced cerebral concentration of myo-Inositol. We examined whether myo-Inositol levels provide a potential marker for depressive symptoms in schizophrenia similar to that in MDD and are informative regarding causal biological pathways underlying both depression and schizophrenia. We used proton magnetic resonance spectroscopy to examine myo-Inositol levels in the anterior cingulate cortex (ACC) in 59 schizophrenia spectrum disorder (SSD) patients and 69 matched community comparison participants. Participants completed the Maryland Trait and State Depression (MTSD) scale to measure symptoms of depression experienced around time of assessment ('State' subscale) and longitudinally ('Trait' subscale). Myo-Inositol in the ACC was negatively correlated with MTSD-Trait scores in both patients (ρ=−0.336, p=0.009) and community comparison samples (ρ=−0.328, p=0.006). Furthermore, patients with a diagnosis of schizoaffective disorder or a history of at least one major depressive episode had lower levels of myo-Inositol compared with schizophrenia patients without a current or past affective diagnosis (p=0.012). Since reduced brain myo-Inositol is associated with MDD, myo-Inositol may be a biochemical marker of depressive mood symptoms across diagnostic boundaries. If confirmed, this finding may aid investigation of the pathophysiology and therapeutics of depression common between depression, schizophrenia and other psychiatric diagnoses. [ABSTRACT FROM AUTHOR]

The major excitatory and inhibitory neurotransmitters, glutamate (Glu) and gamma-aminobutyric acid (GABA), respectively, are implicated in the pathophysiology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide that modulates the Glu system, may also be altered in schizophrenia. This study investigated GABA, Glu + glutamine (Glx), and NAAG levels in younger and older subjects with schizophrenia. Forty-one subjects, 21 with chronic schizophrenia and 20 healthy controls, participated in this study. Proton magnetic resonance spectroscopy (1H-MRS) was used to measure GABA, Glx, and NAAG levels in the anterior cingulate (AC) and centrum semiovale (CSO) regions. NAAG in the CSO was higher in younger schizophrenia subjects compared with younger control subjects. The opposite pattern was observed in the older groups. Glx was reduced in the schizophrenia group irrespective of age group and brain region. There was a trend for reduced AC GABA in older schizophrenia subjects compared with older control subjects. Poor attention performance was correlated to lower AC GABA levels in both groups. Higher levels of CSO NAAG were associated with greater negative symptom severity in schizophrenia. These results provide support for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia. The study also highlights the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia. [ABSTRACT FROM PUBLISHER]

Abnormal hippocampal function likely contributes to relational learning deficits observed in schizophrenia. It is unknown whether these deficits can be attenuated with a training intervention. The purpose of this project was to determine if training could facilitate relational learning of the transverse patterning task in schizophrenia. Healthy and schizophrenia subjects completed a version of transverse patterning that incorporated training. The majority of subjects with schizophrenia successfully learned transverse patterning when provided with training. A subgroup (approximately 25%) of schizophrenia subjects showed no tendency to learn with training. These results were replicated in a second study with a separate cohort and different stimuli. This study illustrates that relational learning of the transverse patterning can be facilitated in schizophrenia with training. [ABSTRACT FROM AUTHOR]

Abstract: Objective: An abnormally increased activation in anterior brain networks, accompanied by normal task performance, has been reported in studies on biological mechanisms of obsessive–compulsive disorder (OCD). We test a hypothesis, that this phenomenon, deemed specific to OCD, will be compromised by a very difficult task, which may lead to reduced cortical information processing and erroneous performance, as found in other disorders such as schizophrenia. Methods: We designed a new variant of high-conflict Stroop-word-color interference task (Stroop-WCIT) with each incongruent (INC) trial preceded by multiple congruent trials. Event-related potentials (ERPs) were acquired from subjects with OCD and case-matched healthy controls (C). We analyzed ERPs elicited by correct responses to conflict-related INC trials. Results: Our hypothesis found no support. Although the anterior ERPs N200, a negative component within 140–300ms latency window, was significantly abnormally increased in OCD subjects, their performance accuracy remained normal. Conclusions: Current findings suggest an enhanced adaptive top-down control in OCD mediated by the prefrontal lateral and dorsal anterior cingulate networks. Significance: Further studies are warranted to test the hypothesis that increased activity within the anterior network for top-down inhibitory control in OCD may be a part of an adaptive compensatory neural mechanism. [Copyright &y& Elsevier]

Schizophrenia can be classified into two separate syndromes: deficit and nondeficit. Primary, enduring negative symptoms are used to define the deficit form of the illness, which is believed to have a unique neurobiological substrate. Previous research suggests that an aberrant prefrontal–thalamic–parietal network underlies deficit schizophrenia. In this study we conducted diffusion tensor imaging (DTI) fiber tracking to assess the integrity of the superior longitudinal fasciculus (SLF), the major white matter tract that connects prefrontal and parietal cortical regions, in deficit and nondeficit people with schizophrenia. We also used proton magnetic resonance spectroscopy (1H-MRS) to assess neurochemistry in the left middle prefrontal and left inferior parietal cortical regions. A total of 20 subjects with schizophrenia (10 deficit and 10 nondeficit) and 11 healthy subjects participated in this study. Results revealed reduced fractional anisotropy (FA), an index of white matter integrity, in the right hemisphere SLF and frontal white matter in the deficit subjects. There were no differences in MRS metabolite concentrations among groups. To our knowledge, this is the first DTI study to show compromised integrity of the major white matter tract that connects frontal and parietal regions in deficit schizophrenia. These findings provide further support for altered frontal–parietal network in deficit schizophrenia.Neuropsychopharmacology (2009) 34, 1514–1522; doi:10.1038/npp.2008.207; published online 3 December 2008 [ABSTRACT FROM AUTHOR]

Reduced brain N-acetyl-aspartate (NAA) has been repeatedly found in chronic schizophrenia and suggests neuronal loss or dysfunction. However, the potential confounding effect of antipsychotic drugs on NAA has not been resolved. We studied 32 minimally treated schizophrenia patients and 21 healthy subjects with single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the frontal and occipital lobes, caudate nucleus, and cerebellum. Concentrations of NAA, Choline, and Cre were determined and corrected for the proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a randomized-controlled double-blind manner with either haloperidol or quetiapine. 1H-MRS was repeated every 6 months for up to 2 years. There was a group main effect for baseline NAA with lower global NAA in schizophrenia subjects before treatment compared to healthy controls. Global NAA was directly related to measures of global cognitive performance in the whole subject sample. Following treatment with haloperidol or quetiapine, there were no changes in NAA in any of the regions studied. Early in the illness, schizophrenia patients already demonstrate subtle reductions in NAA. Treatment with typical or atypical antipsychotic medications for several months does not result in NAA changes.Neuropsychopharmacology (2008) 33, 2456–2466; doi:10.1038/sj.npp.1301631; published online 19 December 2007 [ABSTRACT FROM AUTHOR]

Abstract: Positron emission tomography (PET) was used to investigate differences in neural plasticity associated with learning a unique motor task in patients with schizophrenia and healthy volunteers. Working with a robotic manipulandum, subjects learned reaching movements in a force field. Visual cues were provided to guide the reaching movements. PET rCBF measures were acquired while participants learned the motor skill over successive runs. The groups did not differ in behavioral performance but did differ in their rCBF activity patterns. Healthy volunteers displayed blood flow increases in primary motor cortex and supplementary motor area with motor learning. The patients with schizophrenia displayed an increase in the primary visual cortex with motor learning. Changes in these regions were positively correlated with changes in each group''s motor accuracy, respectively. This is the first study to employ a unique arm-reaching motor learning test to assess neural plasticity during multiple phases of motor learning in patients with schizophrenia. The patients may have an inability to rapidly tune motor cortical neural populations to a preferred direction. The visual system, however, appears to be highly compensated in schizophrenia and the inability to rapidly modulate the motor cortex may be substantially corrected by the schizophrenic group''s visuomotor adaptations. [Copyright &y& Elsevier]

Hypofunction of the N-methyI-D-aspartate receptor (NMDAR) may be involved in the pathophysiology of schizophrenia. NMDAR antagonists like ketamine induce schizophrenia-like features in humans. In rodent studies, NMDAR antagonism impairs learning by disrupting long-term potentiation (LTP) in the hippocampus. This study investigated the effects of ketamine on spatial learning (acquisition) vs retrieval in a virtual Morris water task in humans. Verbal fluency, working memory, and learning and memory of verbal information were also assessed. Healthy human subjects participated in this double-blinded, placebo-controlled study. On two separate occasions, ketamine/placebo was administered and cognitive tasks were assessed in association with behavioral ratings. Ketamine impaired learning of spatial and verbal information but retrieval of information learned prior to drug administration was preserved. Schizophrenia-like symptoms were significantly related to spatial and verbal learning performance. Ketamine did not significantly impair attention, verbal fluency, or verbal working memory task performance. Spatial working memory was slightly impaired. In conclusion, these results provide evidence for ketamine's differential impairment of verbal and spatial learning vs retrieval. By using the Morris water task, which is hippocampal-dependent, this study helps bridge the gap between nonhuman animal and human NMDAR antagonism research. Impaired cognition is a core feature of schizophrenia. A better understanding of NMDA antagonism, its physiological and cognitive consequences, may provide improved models of psychosis and cognitive therapeutics. [ABSTRACT FROM AUTHOR]

Clinical and preclinical studies with NMDA antagonists show that midbrain dopaminergic projections to the prefrontal cortex are sensitive to disturbances in glutamatergic input from the frontal cortex. Schizophrenia might be attributed, in part, to diminished NMDA receptor function and a “downstream” disturbance in dopaminergic response, which corrupts glutamatergic modulation. The inability of individuals with schizophrenia to switch resources with environmental demands might arise, in part, from a failure in glutamate–dopamine circuit dynamics. Drugs that enhance glutamatergic function at non-NMDA sites can offer promise as adjunctive therapeutic agents. [Copyright &y& Elsevier]

Objective: The authors' goal was to test in humans the hypothesis that N-methyl-D-aspartate receptor (NMOAR) antagonism results in increased cortical glutamate activity, as proposed by the NMDAR hypofunction model of schizophrenia. Method: 4-T 1H proton magnetic resonance spectroscopy 1H- MRS) was used to acquire in vivo spectra from the bilateral anterior cingulate of 10 healthy subjects while they received a subanesthetic dose of either placebo or ketamine, an NMDAR antagonist. Assessments given before and after ketamine or placebo administration included the Brief Rating Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, the Clinician-Administered Dissociative States Scale, and the Stroop task. Results: As predicted, there was a significant increase in anterior cingulate glutamine, a putative marker of glutamate neurotransmitter release, with ketamine administration. This increase was not related to schizophrenia-like positive or negative symptoms but was marginally related to Stroop performance. Conclusions: In humans as in animals, an acute hypofunctional NMDAR state is associated with increased glutamatergic activity in the anterior cingulate. [ABSTRACT FROM AUTHOR]

Summary Background The etiopathophysiology of schizophrenia has long been linked to stress and the influence of stress is important in all stages of the illness. Previous examinations of perceived stress and acute stress responses may not capture this longitudinal stress pathophysiology. We hypothesized that the cumulative negative effects of stress, indexed by allostatic load (AL), would be elevated in schizophrenia, and that the AL paradigm would be relevant to our understanding of pathophysiology in schizophrenia. Methods We assessed allostatic load in 30 patients with schizophrenia (SZ; mean age = 33; 17 males) and 20 healthy controls (HC; mean age = 35; 12 males) using 13 cardiovascular, metabolic, neuroendocrine and immune biomarkers. Participants’ perceived stress over the past month, functional capacity and psychiatric symptoms were also measured. Results Controlling for age, SZ had significantly higher AL as compared to HC ( p = 0.007). Greater AL was present in both early course and chronic SZ, and was associated with reduced functional capacity ( p = 0.006) and more psychotic symptoms ( p = 0.048) in SZ. Current level of perceived stress was not significantly elevated in SZ or associated with AL in either group. Conclusions The higher AL found in SZ may reflect increased bodily “wear and tear”, possibly caused by more chronic stress exposure or maladaptive responses to stress over time, although additional research is required to differentiate these causes. The higher AL is similarly present in early and chronic SZ, suggesting primary maladaptive stress physiology rather than secondary effects from medications or chronic illness. [ABSTRACT FROM AUTHOR]

Impaired tolerance to distress may help explain part of the cognitive and functional impairments in schizophrenia (SZ). This project investigated distress intolerance in SZ patients as compared to controls, and whether distress intolerance represented an independent domain in relationship to symptoms, cognition, and functional capacity. Healthy controls ( n =43) and SZ ( n =65) completed a psychological distress challenge experiment and their levels of intolerance to distress were estimated. SZ showed increased distress intolerance such that they were significantly more likely to terminate the distress challenge session early compared to controls. Greater distress intolerance was associated with reduced functional capacity and worse cognitive performance in SZ. Mediation analyses suggested that distress intolerance had an independent effect on functional capacity, while some of this effect was mediated by cognitive performance. Our results suggest that distress intolerance is a promising domain for treatment research, and functional capacity may be improved by targeting treatments towards SZ patient׳s ability to tolerate distress. [ABSTRACT FROM AUTHOR]

Background: Elevated rate of aging-related biological and functional decline, termed “accelerated aging,” is reported in patients with schizophrenia (SCZ) and major depressive disorder (MDD). We used diffusion tensor imaging derived fractional anisotropy (FA) as a biomarker of aging-related decline in white matter (WM) integrity to test the hypotheses of accelerated aging in SCZ and MDD. Methods: The SCZ cohort comprised 58 SCZ patients and 60 controls (aged 20–60 years). The MDD cohort comprised 136 MDD patients and 351 controls (aged 20–79 years). The main outcome measures were the diagnosis-by-age interaction on whole-brain-averaged WM FA values and FA values from 12 major WM tracts. Results: Diagnosis-by-age interaction for the whole-brain average FA was significant for the SCZ (p = .04) but not the MDD (p = .80) cohort. Diagnosis-by-age interaction was nominally significant (p<.05) for five WM tracts for SCZ and for none of the tracts in the MDD cohort. Tract-specific heterochronicity of the onset of age-related decline in SCZ demonstrated strong negative correlations with the age-of-peak myelination and the rates of age-related decline obtained from normative sample (r =−.61 and−.80, p<.05, respectively). No such trends existed for MDD cohort. Conclusions: Cerebral WM showed accelerated aging in SCZ but not in MDD, suggesting some difference in the pathophysiology underlying their WM aging changes. Tract-specific heterochronicity of WM development modulated presentation of accelerated aging in SCZ: WM tracts that matured later in life appeared more sensitive to the pathophysiology of SCZ and demonstrated more susceptibility to disorder-related accelerated decline in FA values with age. This trend was not observed in MDD cohort. [ABSTRACT FROM AUTHOR]

Reduced frontal N-acetylaspartate (NAA) has been repeatedly found in chronic schizophrenia and suggests neuronal loss or dysfunction. However, the potential confounding effect of antipsychotic drugs on NAA has not been resolved. The few studies of antipsychotic-naı̈ve patients are inconclusive. A recent report suggests that antipsychotic drugs may increase NAA in the dorsolateral prefrontal cortex (DLPFC). We studied 10 minimally treated (less than 3 weeks lifetime exposure) schizophrenia patients and 10 normal controls with single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the left frontal and occipital lobes. Concentrations of NAA, Cho, and Cre were determined and corrected for the proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a randomized-controlled double-blind design with either haloperidol or quetiapine. 1H-MRS was repeated within a year. There were no differences in frontal or occipital NAA between patients and controls at baseline. However, frontal NAA was reduced in the schizophrenia group within the first year of treatment. Patients had a clear clinical response to treatment but changes in frontal NAA were not correlated with symptom improvement. The well-described reduced frontal NAA in schizophrenia may not be a trait of the illness but may represent medication effect or progression of the disease. [Copyright &y& Elsevier]

Up to 80% of patients with schizophrenia experience sleep disturbances, which negatively impact daytime functioning. Given that the glutamatergic system is involved in the pathophysiology of schizophrenia as well as normal sleep-wake neurobiology, the current project aimed to determine whether sleep quality was related to brain glutamate levels in schizophrenia. The Pittsburgh Sleep Quality Index (PSQI) was used to assess subjective sleep quality and proton magnetic resonance spectroscopy (MRS) was used to quantify glutamate in the bilateral anterior cingulate, left parietal cortex, and left hippocampus. Results indicate that global PSQI scores were negatively correlated with the anterior cingulate and parietal glutamate levels. In patients with schizophrenia, poorer sleep quality correlated with greater positive symptom severity. Our findings suggest that poor sleep quality is related to greater positive symptom severity and lower levels of anterior cingulate glutamate in individuals with schizophrenia. Interventions to enhance sleep quality may prove beneficial for patients. Future studies will examine whether glutamate relates to objective measures of sleep quality, and whether glutamate may mediate the relationship between sleep quality and symptom severity across the schizophrenia-spectrum. [ABSTRACT FROM AUTHOR]

Cognitive mechanisms underlying auditory hallucinations (AH) in schizophrenia have been related to working memory (WM), although the formative mechanism is unknown. The phonological loop refers to subvocal rehearsals of information held online for supporting WM. As WM deficiency is frequent in schizophrenia, we hypothesized that AH and WM deficit share a common dysfunction in phonological loop operation, especially when it is taxed by ambiguous auditory and verbal associations. We developed an active phonological priming (APP) paradigm in which participants generated arbitrary verbal associations to pseudowords with ambiguous meaning. They were later asked to rate their familiarity to each pseudoword, a task that required subvocal evaluation of ambiguous auditory-verbal information. Factor and mediation analyses were used to test the hypothesis that WM, AH, and APP induced phonological bias toward perceiving ambiguous contents as familiar may share a common underlying mechanism. In 32 patients with schizophrenia (SZ) and 20 healthy controls (HC), SZ rated ambiguous pseudowords as significantly more familiar compared with HC (p = .006), indicating a proneness to APP-induced bias. This increased subjective bias to perceive ambiguous contents as familiar after APP significantly correlated with AH severity (p = .001) and mediated the relationship between WM and AH. Factor analysis demonstrated a common latent factor among WM, AH, and the bias induced by active priming to ambiguous contents. A heightened phonological loop priming to ambiguous contents appears to be mechanistically linked to WM deficits and AH in schizophrenia. These findings emphasize the importance of jointly addressing WM deficits and AH in clinical practice and research. (PsycINFO Database Record (c) 2019 APA, all rights reserved). [ABSTRACT FROM AUTHOR]

Memory is robustly impaired in schizophrenia (SZ) and related to functional outcome. Memory dysfunction has been shown to be related to altered brain glucose metabolism and brain insulin resistance in animal models and human studies of Alzheimer's disease. In this study, differences in brain glucose using magnetic resonance spectroscopy (MRS) and blood Extracellular Vesicle (EV) biomarkers of neuronal insulin resistance (i.e. Akt and signaling effectors) between SZ and controls were investigated, as well as whether these measures were related to memory impairments. Neuronal insulin resistance biomarkers showed a trend for being lower in SZ compared to controls, and memory measures were lower in SZ compared to controls. Occipital cortex glucose was higher in SZ compared to controls indicating lower brain glucose utilization. Linear regression analyses revealed significant relationships between neuronal insulin resistance biomarkers, memory measures, and brain glucose. More specifically, p70S6K, an insulin signaling effector, was related to verbal learning and brain MRS glucose in the SZ group. For the first time, we show that memory impairments in SZ may be related to brain glucose and brain insulin resistance. These data suggest that brain insulin resistance may play a role in the pathophysiology of learning and memory dysfunction in SZ. [ABSTRACT FROM AUTHOR]

Abstract Background Inhibitory deficits in motor cortex in schizophrenia have been well demonstrated using short-interval intracortical inhibition (SICI) by transcranial magnetic stimulation. However, it remains unknown whether these deficits originate from dysfunction of motor cortex itself or reflect abnormal modulations of motor cortex by other schizophrenia-related brain areas. Methods The study was completed by 24 patients with schizophrenia spectrum disorders and 30 healthy control subjects. SICI was obtained by delivering transcranial magnetic stimulation over the left motor cortex. Resting-state functional magnetic resonance imaging and diffusion tensor imaging fractional anisotropy were used to measure functional connectivity (FC) and white matter microstructures, respectively. Stimulation sites for SICI at motor cortex were used as the seeds to obtain whole-brain FC maps. Clinical symptoms were assessed with the Brief Psychiatric Rating Scale. Results In schizophrenia, left prefrontal cortex–motor cortex FC was inversely associated with SICI but positively associated with the underlying white matter microstructure at the left corona radiata and also associated with overall symptoms (all corrected p <.05). Mediation analysis showed that the prefrontal-motor cortex FC significantly mediated the corona radiata white matter effects on SICI (p =.007). Conclusions Higher resting-state left prefrontal-motor cortex FC, accompanied by a higher fractional anisotropy of left corona radiata, predicted fewer inhibitory deficits, suggesting that the inhibitory deficits in motor cortex in schizophrenia may in part be mediated by a top-down prefrontal influence. SICI may serve as a robust biomarker indexing inhibitory dysfunction at anatomic as well as circuitry levels in schizophrenia. [ABSTRACT FROM AUTHOR]

Structural imaging studies have consistently found reduced gray matter thickness of the cerebral cortex in schizophrenia, a finding that is evident in first episode psychosis and may be progressive in some cases. Although genetic predisposition and medication effects may contribute to cortical thinning, we hypothesize that the cumulative effects of stress may represent an environmental factor impacting brain morphology in schizophrenia. We examined the relationship between allostatic load, an index of peripheral biomarkers representing the cumulative effects of stress, and cortical thickness. Allostatic load was calculated for 44 patients with schizophrenia spectrum disorders (SSD) and 33 normal controls (NC) based on 13 cardiovascular, neuroendocrine, immune, and metabolic measurements. Controlling for age, SSD had significantly elevated allostatic load as compared with NC (p = 0.008). Controlling for age, whole brain average cortical thickness was lower in SSD patients compared to NC (p = 0.008). However, once allostatic load was accounted for, the group difference in cortical thickness became marginal (p = 0.058). Exploratory analyses on subcomponents of allostatic load suggested that elevated immune marker C-reactive protein, stress hormones, and cardiovascular indices within allostatic load were more strongly associated with reduced cortical thickness in SSD. In NC, only the association between immune marker C-reactive protein and cortical thickness was replicated. These results support the hypothesis that allostatic load may account for some of the gray matter deficits observed in schizophrenia. Among the allostatic indices, the inflammatory mechanism appears particularly relevant to cortical thickness in both schizophrenia patients and normal controls. [ABSTRACT FROM AUTHOR]

Glucocorticoid and immune pathways typically interact dynamically to optimize adaptation to stressful environmental challenges. We tested the hypothesis that a dysfunctional glucocorticoid–immune relationship contributes to abnormal stress response in schizophrenia. Saliva samples from 34 individuals with schizophrenia (20 male, 14 female) and 40 healthy controls (20 male, 20 female) were collected prior to and at 3 time points following completion of a computerized psychological challenge meant to be frustrating. Salivary concentrations of cortisol and interleukin-6 (IL-6) and their response to the challenge were examined. Both cortisol and IL-6 significantly increased in response to stress in the combined sample (both p < .05). In controls, the rise in cortisol following the challenge was negatively correlated to the subsequent changes in IL-6 ( r = −.461, p = .003), such that rise of cortisol immediately after stress predicts subsequently lower IL-6 levels. In contrast, this relationship was positive in schizophrenia patients ( r = .379, p = .027). The trends were significantly different ( Z = 3.7, p = .0002). This stress paradigm induces a rise in both cortisol and IL-6. In healthy controls, a more robust acute cortisol response was associated with a steeper decline of IL-6 levels following stress, corresponding to the expected anti-inflammatory effects of cortisol. Patients exhibited the opposite relationship, suggesting an inability to down-regulate inflammatory responses to psychological stress in schizophrenia; or even a paradoxical increase of IL-6 response. This finding may partially underlie abnormalities in inflammatory and stress pathways previously found in the illness, implicating dysregulated stress response in the chronic inflammatory state in schizophrenia. [ABSTRACT FROM AUTHOR]

In vivo measurement of neurotransmitters and modulators is now feasible with advanced proton magnetic resonance spectroscopy ( 1 H MRS) techniques. This review provides a basic tutorial of MRS, describes the methods available to measure brain glutamate, glutamine, γ-aminobutyric acid, glutathione, N -acetylaspartylglutamate, glycine, and serine at magnetic field strengths of 3 T or higher, and summarizes the neurochemical findings in schizophrenia. Overall, 1 H MRS holds great promise for producing biomarkers that can serve as treatment targets, prediction of disease onset, or illness exacerbation in schizophrenia and other brain diseases. [ABSTRACT FROM AUTHOR]

Introduction Diffusion tensor imaging (DTI) studies in patients with schizophrenia have shown abnormalities in the microstructure of white matter tracts. Specifically, reduced fractional anisotropy (FA) has been described across multiple white matter tracts, in studies that have mainly included patients treated with antipsychotic medications. Objective To compare FA in antipsychotic-naïve patients experiencing a first episode of psychosis (FEP) to FA in healthy controls to demonstrate that the variance of FA can be grouped, in a coincidental manner, in four predetermined factors in accordance with a theoretical partition of the white matter tracts, using a principal components analysis (PCA). Methods Thirty-five antipsychotic-naïve FEP patients and 35 age- and gender-matched healthy controls underwent DTI at 3 T. Analysis was performed using a tract-based spatial statistics (TBSS) method and exploratory PCA. Results DTI analysis showed extensive FA reduction in white matter tracts in FEP patients compared with the control group. The PCA grouped the white matter tracts into four factors explaining 66% of the total variance. Comparison of the FA values within each factor highlighted the differences between FEP patients and controls. Discussion Our study confirms extensive white matter tracts anomalies in patients with schizophrenia, more specifically, in drug-naïve FEP patients. The results also indicate that a small number of white matter tracts share common FA anomalies that relate to deficit symptoms in FEP patients. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in FEP patients. [ABSTRACT FROM AUTHOR]

Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age = 18-63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p < 0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia. [ABSTRACT FROM AUTHOR]

We hypothesized that reduced fractional anisotropy (FA) of water diffusion and its elevated aging-related decline in schizophrenia patients may be caused by elevated hyperintensive white matter (HWM) lesions, by reduced permeability-diffusivity index (PDI), or both. We tested this hypothesis in 40/30 control/patient participants. FA values for the corpus callosum were calculated from high angular resolution diffusion tensor imaging (DTI). Whole-brain volume of HWM lesions was quantified by 3D-T2w-fluid-attenuated inversion recovery (FLAIR) imaging. PDI for corpus callosum was ascertained using multi b-value diffusion imaging (15 b-shells with 30 directions per shell). Patients had significantly lower corpus callosum FA values, and there was a significant age-by-diagnosis interaction. Patients also had significantly reduced PDI but no difference in HWM volume. PDI and HWM volume were significant predictors of FA and captured the diagnosis-related variance. Separately, PDI robustly explained FA variance in schizophrenia patients, but not in controls. Conversely, HWM volume made equally significant contributions to variability in FA in both groups. The diagnosis-by-age effect of FA was explained by a PDI-by-diagnosis interaction. Post hoc testing showed a similar trend for PDI of gray mater. Our study demonstrated that reduced FA and its accelerated decline with age in schizophrenia were explained by pathophysiology indexed by PDI, rather than HWM volume. [ABSTRACT FROM AUTHOR]

Abstract: Learning and memory impairments are present in schizophrenia (SZ) throughout the illness course and predict psychosocial function. Abnormalities in prefrontal and hippocampal function are thought to contribute to SZ deficits. The radial arm maze (RAM) is a test of spatial learning and memory in rodents that relies on intact prefrontal and hippocampal function. The goal of the present study was to investigate spatial learning in SZ using a virtual RAM. Thirty-three subjects with SZ and thirty-nine healthy controls (HC) performed ten trials of a virtual RAM task. Subjects attempted to learn to retrieve four rewards each located in separate arms. As expected, subjects with SZ used more time and traveled more distance to retrieve rewards, made more reference (RM) and working memory (WM) errors, and retrieved fewer rewards than HC. It is important to note that the SZ group did learn but did not reach the level of HC. Whereas RM errors decreased across trials in the SZ group, WM errors did not. There were no significant relationships between psychiatric symptom severity and maze performance. To our knowledge, use of a virtual 8-arm radial maze task in SZ to assess spatial learning is novel. Impaired virtual RAM performance in SZ is consistent with studies that examined RAM performance in animal models of SZ. Results provide further support for compromised prefrontal and hippocampal function underlying WM and RM deficits in SZ. The virtual RAM task could help bridge preclinical and clinical research for testing novel drug treatments of SZ. [Copyright &y& Elsevier]